Pharma's R&D Focus Shifting to Stem Cells

Investors' Interest in These Cells Increases as Scientists Continue to Unleash Their Potential

Stem cells could replace and potentially improve upon at least some in vivo models in drug discovery and development. That was a key message from the “World Stem Cells and Regenerative Medicine Congress” held recently in London.

“There is a major focus now on stem cells in pharma R&D with the major investors showing an interest,” according to Ian Cotgreave, Ph.D., director of molecular toxicology and safety assessment at AstraZeneca. He noted that pharma’s current focus is on cardiomyocytes and hepatocytes, as well as on differentiation protocols and understanding phenotypic progression.

There is also increasing interest in induced pluripotent stem cells (iPSCs). However, despite all this activity, there is still a long way to go before functional stem cell-based screening is involved in making any decisions about compounds. Going forward, there will be a need to accentuate academic-industry collaborations with a focus upon compound validation sets and frequent reality checks. Dr. Cotgreave observed that there is a window open for these collaborations, but he predicts that it will close within five years.

Screening needs go well beyond application to cardiomyocytes and hepatocytes, he said, because there are other major causes of attrition that cannot currently be met by stem cell models, such as neurological/neuropsychiatric and gastrointestinal adverse effects. There is also an issue over which stem cell models are really fit for purpose. For instance, the liver is subject to many complex pathologies, and it is not clear how well stem cell-derived hepatocytes might model these.

The pharmaceutical industry can provide well-annotated compound sets for validation of stem cell screens. Dr. Cotgreave mentioned that AstraZeneca has been working with Cellartis on this, using human embryonic stem cell (hESC)-derived hepatocytes, and is now awaiting some results from high-content biology measurements.

The compounds in the AstraZeneca set range from very toxic to harmless, he explained, so the output should be particularly informative, and the company is now extending the work to cardiomyocytes. AstraZeneca is a member of the Stem Cells for Safer Medicines initiative a U.K.-based public-private partnership aiming to provide screening tools for safety assessment.

Annamaria Rossi, Ph.D., director of drug safety at Pfizer, said her department is evaluating stem cells as a new tool for toxicity prediction and also to support Pfizer’s flagship regenerative medicine unit. “There are two main reasons for late failure of compounds—toxicity and lack of efficacy. Stem cells can help by predicting these qualities earlier and in a better way by identifying human populations to treat—or not to treat—and they will also help in translation from molecular target to clinical development.”

The ideal in vitro stem cell system would be easy to culture, have unlimited availability, and be predictive of human toxicity. In these respects, stem cells are not a perfect model, although much progress has been made. “We need to improve predictivity of these models so we are working on keeping the cells’ morphology using 3-D models or co-culture. We also want to do comparisons of our stem cells with other adult organs and cells,” Dr. Rossi explained.

Discussions with regulatory agencies are necessary in order to determine whether in vitro systems can actually substitute animal testing. Some progress is evident as an embryonic stem cell toxicity test validated several years ago by the European Centre for the Validation of Alternative Methods is now being reviewed by the FDA to see if it can actually replace an in vivo test.

Meanwhile, Kyle Kolaja, Ph.D., research director of early safety assessment at Roche has been working with stem cell-derived cardiomyocytes.“We have been using the same tools for the last 40 to 50 years to predict what will happen in the clinic.” There is a need for a stronger connection to the disease setting in human biology, and it is easier to make cardiomyocytes than hepatocytes.

Roche is also a partner in SC4SM and has collaborations under way with Cellular Dynamics International (CDI), Massachusetts General Hospital, and iStem. “We’ve really gone out to find as much data and information as possible to leverage this,” said Dr. Kolaja. A key driver is the collaboration with CDI, which has a cell-manufacturing pipeline and ships material for assay development to Roche.

Roche has established a model of primary human cardiomyocytes using immunohistochemistry and gene-expression studies. Its scientists have also learned that ATP is an important marker of cardiotoxicity in these cells. Another aspect of this work is looking at the cells’ electrophysiological properties and ion channels of interest. A key question now is whether there is a single cell target for cardiotoxicity. Dr. Kolaja believes these advances will really change the drug-development process. “We will use more human-relevant material for screening earlier on,” he said.

A stem cell is defined by the capacity to self-renew into an identical stem cell or differentiate into functionally different cells. Stem cells maintain many adult tissues, and there is evidence that some solid tumors are also maintained by a subset of cells with stem cell properties, referred to as tumor-initiating cells or cancer stem cells.

There are two implications of the cancer stem cell theory. First, there is a need to target the right cells so that tumor-initiating cells are not left behind after therapy. Second, the correct cells should be used for drug discovery and screening.

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